Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells
Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells
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DOI：
10.1158/1078-0432.ccr-05-2085
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发表时间：
2006-05-15
影响因子：
11.5
通讯作者：
Kihara, Kazunori
中科院分区：
文献类型：
--
作者：
Yano, Akihiro;Fujii, Yasuhisa;Kihara, Kazunori
目的：糖皮质激素，如泼尼松、氢化可的松和地塞米松，已知对激素不敏感的前列腺癌(HRPC)患者有一定的临床益处。然而，糖皮质激素影响HRPC生长的潜在机制尚不清楚。在此，我们假设糖皮质激素对HRPC的治疗作用可以归因于通过下调两个主要的血管生成因子血管内皮生长因子(VEGF)和白细胞介素8(IL-8)，通过糖皮质激素受体直接抑制血管生成。实验设计：利用表达糖皮质激素受体的DU145检测地塞米松对血管内皮生长因子和IL-8表达及细胞增殖的影响。结果：在常氧条件下，地塞米松可显著下调血管内皮生长因子和IL-8基因表达50%(P<；0.001)和89%(P<；0.001)，并使血管内皮生长因子和IL-8蛋白产生分别减少55%(P<；0.001)和74%(P<；0.001)。同样，氢化可的松下调血管内皮生长因子和IL-8基因的表达。地塞米松的作用可被糖皮质激素受体拮抗剂RU486完全逆转。即使在类低氧条件下，地塞米松也能抑制血管内皮生长因子和IL-8的表达。在DU145移植瘤中，地塞米松显著降低肿瘤体积和微血管密度，下调VEGF和IL-8基因的表达，而不影响细胞的体外增殖。结论：糖皮质激素抑制雄激素非依赖性前列腺癌的生长可能是通过体内直接通过糖皮质激素受体减少VEGF和IL-8的产生，从而抑制肿瘤相关血管的生成。
Purpose: Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8).Experimental Design: The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume.Results: Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% (P < 0.001) and 89% (P < 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% (P < 0.001) and 74% (P < 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and downregulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells.Conclusion: Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptor in vivo.